This research focuses on liver regeneration and the initial triggers of this phenomenon. Bile acids are detergent molecules made from cholesterol which help solubilize fats for absorption in the intestine. Bile acids are made by hepatocytes, excreted into the intestine, and recirculated with little loss each day. The hypothesis of this proposal is that when the uninjured non-cholestatic liver encounters bile acids exceeding the maximum secretory capacity of the liver, regeneration is initiated. Aim 1 will determine the role of bile acids in the initiation of liver regeneration using a model of partial hepatectomy. In Aim 2 a model of bile acid administration through the portal vein will allow the focused study of the effects of supraphysiolgic levels bile acids on the liver in the absence of other injury. Lastly, Aim 3 will examine the contribution of the bile acid influx transporter and nuclear receptor signaling in bile acid-dependent liver regeneration. In summary, these studies will closely examine the effects of bile acids on the unobstructed liver, and determine how bile acids are involved in the triggering of liver regeneration. This proposal describes a five year plan for the development of an academic career in translational research in the field of Hepatology. The prinicipal [sic] investigator has completed a residency in Internal Medicine, a fellowship in Gastroenterology, and a post-doctoral fellowship in a laboratory focused on gene regulation and signal transduction in the context of hepatic inflammation. The proposal will promote the primary investigator's command of molecular biology and physiology as it relates liver regeneration and hepatocarcinogenesis, and prepare him for a career as an independent investigator. Dr. Markus Grompe will mentor the scientific aspects of the proposal, and the primary investigator has assembled a team of advisors who will assist in achieving the scientific and career goals outlined in the proposal. Dr. Grompe is a recognized leader in the field hepatocyte proliferation and is well-equipped to mentor this project. The laboratory is well-funded, has the appropriate equipment and support personnel, and exists in an environment supportive of this type of research at Oregon Health & Sciences University. PUBLIC HEALTH RELEVANCE: This contribution is significant because it is expected to provide a physiological reason for liver regeneration which can be used to manipulate hepatocyte proliferation for the purposes of preventing and treating the most common liver disease states.